title: Msx-1 is suppressed in bisphosphonate-exposed jaw bone analysis of bone turnover-related cell signalling after bisphosphonate treatment.
abstract: OBJECTIVE
  Bone-destructive disease treatments include bisphosphonates and antibodies against receptor activator for nuclear factor κB ligand (aRANKL). Osteonecrosis of the jaw (ONJ) is a side-effect. Aetiopathology models failed to explain their restriction to the jaw. The osteoproliferative transcription factor Msx-1 is expressed constitutively only in mature jaw bone. Msx-1 expression might be impaired in bisphosphonate-related ONJ. This study compared the expression of Msx-1, Bone Morphogenetic Protein (BMP)-2 and RANKL, in ONJ-affected and healthy jaw bone.
  
  
  METHODS
  An automated immunohistochemistry-based alkaline phosphatase-anti-alkaline phosphatase method was used on ONJ-affected and healthy jaw bone samples (n = 20 each): cell-number ratio (labelling index, Bonferroni adjustment). Real-time RT-PCR was performed to quantitatively compare Msx-1, BMP-2, RANKL and GAPDH mRNA levels.
  
  
  RESULTS
  Labelling indices were significantly lower for Msx-1 (P < 0.03) and RANKL (P < 0.003) and significantly higher (P < 0.02) for BMP-2 in ONJ compared with healthy bone. Expression was sevenfold lower (P < 0.03) for Msx-1, 22-fold lower (P < 0.001) for RANKL and eightfold higher (P < 0.02) for BMP-2 in ONJ bone.
  
  
  CONCLUSIONS
  Msx-1, RANKL suppression and BMP-2 induction were consistent with the bisphosphonate-associated osteopetrosis and impaired bone remodelling in BP- and aRANKL-induced ONJ. Msx-1 suppression suggested a possible explanation of the exclusivity of ONJ in jaw bone. Functional analyses of Msx-1- RANKL interaction during bone remodelling should be performed in the future.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Erlangen-Nuremberg, Erlangen, Germany. falk.wehrhan@uk-erlangen.de
authors.forename: F
authors.initials: F
authors.lastname: Wehrhan
authors.forename: P
authors.initials: P
authors.lastname: Hyckel
authors.forename: K
authors.initials: K
authors.lastname: Amann
authors.forename: J
authors.initials: J
authors.lastname: Ries
authors.forename: P
authors.initials: P
authors.lastname: Stockmann
authors.forename: Ka
authors.initials: K
authors.lastname: Schlegel
authors.forename: Fw
authors.initials: F
authors.lastname: Neukam
authors.forename: E
authors.initials: E
authors.lastname: Nkenke
mesh_terms: D000469:Alkaline Phosphatase / Q000032:analysis; D050071:Bone Density Conservation Agents / Q000009:adverse effects*; D055396:Bone Morphogenetic Protein 2 / Q000032:analysis / Q000187:drug effects; D055415:Bone Morphogenetic Protein 4 / Q000032:analysis / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D002452:Cell Count; D004164:Diphosphonates / Q000009:adverse effects*; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects; D007150:Immunohistochemistry; D007571:Jaw Diseases / Q000139:chemically induced* / Q000473:pathology; D051957:MSX1 Transcription Factor / Q000032:analysis / Q000187:drug effects*; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D010011:Osteocytes / Q000187:drug effects / Q000473:pathology; D010020:Osteonecrosis / Q000139:chemically induced* / Q000473:pathology; D010022:Osteopetrosis / Q000139:chemically induced; D000077268:Pamidronate; D053245:RANK Ligand / Q000032:analysis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D000077211:Zoledronic Acid
chemical_list: C525718:BMP2 protein, human; C525809:BMP4 protein, human; D050071:Bone Density Conservation Agents; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D004164:Diphosphonates; D007093:Imidazoles; D051957:MSX1 Transcription Factor; C484083:MSX1 protein, human; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D000077211:Zoledronic Acid; D000469:Alkaline Phosphatase; D000077268:Pamidronate